Megan HandleyPharmD Candidate Class of 2015Drug Information Question

Polymyxin B sulfate stability and compatibility with bacitracin for injection

Polymyxin B for injection Package Insert (Sagent) “Polymyxin B sulfate solutions for parenteral use should be stored under refrigeration and any unused

portion should be discarded within 72 hours.” Dosage and Administration

o Parenteral: Dissolve 500,000 polymyxin B units in 300-500 mL of 5% Dextrose Injection for

continuous intravenous dripo Intramuscular:

Dissolve 500,000 polymyxin B units in 2 mL sterile water for injection or 0.9% sodium chloride or procaine hydrochloride injection 1%

o Intrathecal Dissolve 500,000 polymyxin B units in 10 mL 0.9% sodium chloride injection for 50,000

units per mL dosage Storage Recommendations

o After reconstitution, product must be stored under refrigeration, between 2º and 8ºC (36º and 46º F) and any unused portion should be discarded after 72 hours.

Stability of polymyxin B sulfate diluted in 0.9% sodium chloride injection and stored at 4 or 25º C (He et al.)

The study analyzed the stability of polymyxin B in infusion bags containing 0.9% sodium chloride at room temperature and under refrigeration

They found that on average, the samples retained over 90% of their initial concentration for up to two days at both storage temperatures.

All samples retained over 90% of their initial concentration at 24 hours The decomposition kinetics of polymyxin B in infusion bags containing 0.9% sodium chloride injection

exhibited pseudo-first-order kineticso Rate constants of 0.024-0.075 day-1 at 25ºC (loss of 2.4-7.5% concentration daily)o Rate constants of 0.022-0.043 day-1 at 4ºC (loss of 2.2-4.3% concentration daily)

Polymyxin B was stable for at least 1 day when stored at 4 or 25ºC in infusion bags containing 0.9% sodium chloride injection.

o Stability did not significantly differ between the two temperatures. Table 1 and Table 2 (attached) in the study break down the various manufacturers and lot numbers and

report the percentage of the original concentration of polymyxin b sulfate that remains each day. Results are reported for both 4 and 25ºC.

Based upon this study, I would keep all reconstituted polymyxin B in the refrigerator to lengthen its stability. I also would discard the reconstituted product 48 hours after reconstitution. It would also be good practice to make sure all employees note the day and exact time the product was reconstituted so it can be discarded appropriately.

MICROMEDEX IV Compatibility Analysis Solutions reported to be compatible with polymyxin B include Dextrose 5%, Normal Saline (sodium

chloride 0.9%), and invert sugar 7.5% with electrolytes.

The compatibility detail for polymyxin B sulfate (0.0564-0.078 mg/mL) and normal saline (sodium chloride 0.9%), cited the He et al. as their source for the reported stability of polymyxin B in sodium chloride solution.

The information specifies: All samples retained over 90% of their original concentration at 24 hours. Within 48 hours, the concentrations in some samples exhibited greater than 10% loss in concentration, with one sample having 17% lost.

Bacitracin is not on the Micromedex list of compatible medications for IV treatment with polymyxin B. Dactinomycin, daptomycin, octreotide, and cyclosporine are alternative cyclic peptides that are compatible with polymyxin B sulfate for intravenous therapy.

SummaryOverall, there is very limited research thus far regarding the stability of polymyxin B sulfate in normal

saline solution. The package insert mentioned above does mention that polymyxin B can be reconstituted with normal saline; however the storage recommendations do not specify a certain time period for each diluent. They simply apply a 72 hour limit on all reconstituted solutions of polymyxin B, which is the known time for polymyxin B to lose stability in 5% dextrose.

He et al. conducted a study determining how much time must elapse for a solution of polymyxin B sulfate in sodium chloride injection to reach a concentration of less than 90% of its original strength. Since this study was specific to normal saline as a diluent, the results may in turn be more specific than those mentioned in the package insert. They determined polymyxin B sulfate was stable after reconstitution for at least 1 day when stored at either 4 or 25ºC (stability being defined as greater than 90% of the original concentration of polymyxin B.) Most solutions maintained greater than 90% of their concentration after 48 hours, with the exception of some samples. More samples of polymyxin B in normal saline bags maintained a stable concentration after 48 days if they were refrigerated; however, the difference between the two groups was not statistically significant.